Original generic name for Kadcyla was trastuzumab emtansine (established by the US Adopted Name [USAN] Council).10031006 Because of similarity between the original generic name for Kadcyla (trastuzumab emtansine) and the generic name for Herceptin (trastuzumab), FDA approved the prefix addition “ado” to the generic name for Kadcyla (i.e., ado-trastuzumab emtansine).10041005 However, potential exists for dispensing or prescribing errors involving these drugs.1001100410051006

Exercise extra care to ensure accuracy of prescriptions.1001100210051006 Institute for Safe Medication Practices (ISMP), FDA, and the manufacturer of ado-trastuzumab emtansine (Kadcyla) recommend that prescribers communicate both brand and generic names for ado-trastuzumab emtansine (Kadcyla) on prescription order forms.1001100210051006 (See Possible Prescribing and Dispensing Errors under General Precautions, in Cautions.)

Introduction

Uses for Trastuzumab

Breast Cancer

Use as monotherapy for treatment of metastatic breast cancer that has relapsed following prior chemotherapy for metastatic disease in patients with tumors that overexpress the HER2 protein.145162526

Initial treatment of metastatic breast cancer, in combination with paclitaxel, in patients with tumors that overexpress the HER2 protein.1352526

Adjuvant treatment in conjunction with chemotherapy in patients with operable HER2-positive breast cancer†.262829

Evaluation of HER2 status is required prior to initiating therapy.1 (See Evaluation of HER2 under Cautions.) Use only in patients whose tumors overexpress HER2 protein.1Not indicated for use in patients with tumors that do not overexpress the HER2 protein.15

Although the use of trastuzumab in combination with an anthracycline and cyclophosphamide for initial treatment of HER2-overexpressing metastatic breast cancer has been investigated in a large, randomized clinical trial,13 the clinical benefit did not outweigh the increased risk of serious cardiac toxicity and use of this combination regimen did not receive approval from FDA.61719

Trastuzumab Dosage and Administration

General

Observe patients for fever and chills or other infusion-associated symptoms during infusion.1 (See Infusion-related Effects under Cautions.)

Infusion should be interrupted in patients experiencing dyspnea or clinically important hypotension.1 Discontinuance of therapy should be considered strongly in patients who develop ARDS, anaphylaxis, or angioedema.1 Immediately discontinue infusion and initiate appropriate medical treatment if severe trastuzumab-induced reactions occur.124 Patients should be monitored carefully until signs and symptoms have resolved completely.1

Administration

IV Administration

Reconstitution

Reconstitute vial containing 440 mg of lyophilized drug with 20 mL of the supplied bacteriostatic water for injection, containing 1.1% benzyl alcohol to provide a solution containing 21 mg of trastuzumab per mL.122

Alternatively, for patients sensitive to benzyl alcohol, reconstitute using 20 mL of sterile water for injection.1

Handle with care during reconstitution; shaking the reconstituted solution or causing excessive foaming during the addition of diluent may cause problems with dissolution and the amount of the drug that can be withdrawn from the vial.122

Slowly inject 20 mL of diluent into the vial with the stream of diluent directed into the lyophilized cake of trastuzumab.122 Swirl vial gently to aid reconstitution; do not shake reconstituted solution because trastuzumab may be sensitive to shear-induced stress (e.g., agitation, rapid expulsion from a syringe).122

Allow vial to stand undisturbed for 5 minutes following reconstitution; slight foaming of the reconstituted solution is not unusual.122 Reconstituted solution should be clear to slightly opalescent, colorless to pale yellow, and free of visible particulate matter.122

Vials reconstituted with bacteriostatic water for injection should be immediately labeled in the area marked “Do not use after:” with the future date that is 28 days from the date of reconstitution; discard unused portions after 28 days.1

Vials reconstituted with sterile water for injection should be used immediately; discard any unused solution.1

Loading dose of 4 mg/kg followed by maintenance doses of 2 mg/kg once weekly for 51 weeks has been used in clinical studies.28 Trastuzumab was initiated concurrently with paclitaxel after doxorubicin and cyclophosphamide in these studies.28 Other regimens also have been investigated.2930

Discontinue therapy if a clinically important decrease in left ventricular function or CHF occurs.11819 If trastuzumab is used in early breast cancer, therapy interruption may be needed in patients experiencing asymptomatic decreases in left ventricular function.31 Institute appropriate medical therapy if cardiac dysfunction occurs.121

Increased risk of cardiac dysfunction in geriatric patients, patients with preexisting cardiac disease, and patients who have had prior cardiotoxic therapy (e.g., anthracycline therapy or radiation therapy to the chest area).1

Infusion-related Effects

Risk of severe and rarely fatal infusion-related reactions (e.g., bronchospasm, dyspnea, hypoxia, severe hypotension) generally with the first dose (possibly during or immediately following the infusion).124

Risk of symptoms worsening progressively and leading to further pulmonary complications.1

Risk of marked clinical deterioration following initial improvement in those with acute signs and symptoms.1

Hematologic Effects

Risk of leukopenia and anemia especially in those receiving trastuzumab in combination with paclitaxel.1 These reactions occur frequently with combination chemotherapy, but rarely in those receiving monotherapy;1 they are mild to moderate in severity, reversible, and do not require discontinuance of therapy.1

Sensitivity Reactions

Hypersensitivity Reactions

Risk of severe hypersensitivity reactions (e.g., fatal anaphylaxis).124 Signs and symptoms of hypersensitivity reactions include anaphylaxis, urticaria, bronchospasm, angioedema, and/or hypotension.1 Onset usually during initial infusion, but may occur following completion of an infusion.1

If a severe hypersensitivity reaction occurs, interrupt infusion and administer appropriate medical therapy (e.g., epinephrine, corticosteroids, diphenhydramine, bronchodilators, oxygen).1 Monitor patients carefully until signs and symptoms have resolved completely.1 Discontinuance of therapy should be considered strongly in patients who develop anaphylaxis or angioedema.1 Additional infusions may be tolerated following complete recovery, typically accompanied by prophylactic treatment (e.g., antihistamines, corticosteroids); severe reactions may occur despite the use of premedication.1

Administer with caution in patients with known hypersensitivity to trastuzumab, Chinese Hamster Ovary (CHO) cell proteins, or any component of the formulation.1

Possible Prescribing and Dispensing Errors

Ensure accuracy of prescriptions;1001100210051006 similarity in generic name of Herceptin (trastuzumab) and Kadcyla (ado-trastuzumab emtansine) may result in medication errors.1001100410051006 Such errors may be associated with severe toxicity or lack of appropriate therapy.100110041005 (See Special Alerts.)

Specific Populations

Pregnancy

Lactation

Distributed into milk in monkeys; not known whether distributed into human milk.1 Discontinue nursing during trastuzumab therapy and for 6 months following the last dose of the drug because of potential risk to nursing infants.1

Elimination

Metabolism

Elimination Route

Elimination may involve clearance of IgG through the reticuloendothelial system.251819

Half-life

5.8 days (range: 1–32 days) following a loading dose of 4 mg/kg followed by a weekly maintenance dose of 2 mg/kg IV.116 Following IV infusion of 10 or 500 mg of trastuzumab, elimination half-life averaged 1.7 or 12 days, respectively.1

Stability

Storage

Parenteral

Powder for Injection

Reconstituted solutions (in bacteriostatic water for injection containing benzyl alcohol) are stable for 28 days (when refrigerated at 2–8°C).1 Do not freeze.1

Solutions reconstituted with sterile water for injection should be used immediately and unused portions discarded.1

Reconstituted solutions diluted in 0.9% sodium chloride injection are stable for up to 24 hours when prepared and stored in PVC or polyethylene bags at 2–8°C.118

5% dextrose injection should not be used as a diluent for trastuzumab solutions;1 diluents other than those recommended by the manufacturer may not maintain the stability or sterility of the antibody solution.11822

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Binds specifically to the extracellular domain of the HER2 receptor or HER2 protein.1

The HER2 receptor participates in receptor-receptor interactions that regulate cell differentiation, growth, and proliferation.67 Overexpression of the HER2 receptor contributes to the process of neoplastic transformation.67

Trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC) has been demonstrated and occurs preferentially in cells that overexpress the HER2 protein compared with cells that do not.1

Advice to Patients

Patients should be informed of possible delayed24 (after completion of the infusion) severe reactions.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., cardiovascular disease).1

Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.